The present review regarding atypical endometrial hyperplasia (AEH) focused on the main debated factors regarding this challenging clinical condition: (i) predictive variables of occult endometrial cancer (EC); (ii) the rate of EC underestimation according to different endometrial sampling methods; and (iii) the appropriateness of lymph node status assessment. When cancer is detected, approximately 90% of cases include low-risk EC, although intermediate/high-risk cases have been found in 10–13% of women with cancer. Older age, diabetes, high BMI, and increased endometrial thickness are the most recurrent factors in women with EC. However, the predictive power of these independent variables measured on internal validation sets showed disappointing results. Relative to endometrial sampling methods, hysteroscopic endometrial resection (Hys-res) provided the lowest EC underestimation, ranging between 6 and 11%. Further studies, including larger sample sizes of women undergoing Hys-res, are needed to confirm these findings. These data are urgently needed, especially for female candidates for conservative treatment. Finally, the evaluation of lymph node status measured on 660 of over 20,000 women showed a lymph node positivity of 2.3%. Although there has been an increase in the use of this procedure in AEH in recent years, the present data cannot recommend this option in AEH based on a cost/risk/benefit ratio.

Endometrial cancer is the most prevalent gynecologic cancer in the United States and has rising incidence and mortality. Endometrial intraepithelial neoplasia or atypical endometrial hyperplasia (EIN-AEH), a precancerous neoplasm, is surgically managed with hysterectomy in patients who have completed childbearing because of risk of progression to cancer. Concurrent endometrial carcinoma (EC) is also present on hysterectomy specimens in up to 50% of cases. Conservative medical management with progestins and close surveillance can be employed for certain populations after evaluating for concurrent EC. Currently, national professional guidelines recommend an individualized approach based on community access to care and patient factors. There is, however, no US civilian consensus on who should primarily manage EIN-AEH: Physician gynecologic specialists (GSs) and/or gynecologic oncologist (GO) subspecialists. Military health care presents an additional challenge with beneficiaries stationed at remote or overseas locations. While patients may not have local access to a GO subspecialist, many locations are staffed with GSs. Travel for care with a GO incurs additional cost for the patient and the military health care system, removes patients from local support systems, and can impact mission readiness. To provide the best care, optimize clinical outcomes, and avoid over- or under-treatment, military-specific guidelines for EIN-AEH management are needed. We propose a clinical decision tree incorporating both GS and GO subspecialists in the care of military beneficiaries with EIN-AEH. The subject matter expert panel recommends referral of EIN-AEH to a military (preferrable) or civilian GO for management if local access is available within 100 miles[Q1]. If travel of >100 miles is required, the patient should be offered the choice of a military GO referral if available within 250 miles (preferred) versus management by a GS. If travel is >100 miles from a GO or the patient declines a GO referral, the panel recommends that the GS should attempt to exclude concurrent EC by performing a hysteroscopic assessment of the endometrium with a directed biopsy, if not already done. A pelvic ultrasound should be obtained to evaluate the endometrial thickness (>2 cm more likely to harbor EC) along with a secondary gynecologic pathology review with immunohistochemical testing for Lynch syndrome (MLH1, MSH2, MSH6, and PMS2) and p53 expression. If any major additional risk factors are uncovered, the patient should be referred to a GO subspecialist for further management. If no additional major risk factors for concurrent EC are identified and hysteroscopy with expert gynecologic pathology review confirms no presence of EC in the pathology specimen, a virtual consultation and counseling with a military GO can be offered, with local surgical and/or medical management provided by a GS. If on subsequent pathology, EC is identified, the patient should be referred to a GO for further treatment considerations and counseling. Determining the optimal treatment for patients with EIN-AEH is nuanced and, within the military health care system, is complicated by varied access to expert management by a GO subspecialist. Military beneficiaries with this diagnosis present a unique challenge and warrant a standardized approach to maximize clinical outcomes.Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2025. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs.Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations; p53 wt and p53 abn, respectively) were performed on 319 new EC samples. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]).ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P < .001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups; but, otherwise, there were no predictable associations between molecular and ESMO risk groups.Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017;123:802-13. © 2016 American Cancer Society.© 2017 American Cancer Society.

Advanced endometrial cancer (EC) poses significant therapeutic challenges due to molecular heterogeneity and immune evasion. Immune checkpoint inhibitors (ICIs) show promise, particularly in mismatch repair-deficient (MMRd) and POLE-mutated subtypes, but resistance remains a barrier. This review synthesizes recent advances in biomarker-driven immunotherapy for EC, focusing on predictive biomarkers (e.g., LRP2, FANCE, MSH2, miRNA signatures), combination strategies (ICIs with anti-angiogenics or PARP inhibitors), and challenges in clinical translation. We highlight the impact of tumor microenvironment components, emerging technologies like machine learning, and future directions for personalized immunotherapy. Standardizing biomarker testing and optimizing trial designs will be critical to overcome resistance and improve outcomes.

Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis.RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint.A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis.Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.

The purpose of this article is to review the pharmacology, safety, evidence for current use, and potential futures uses for combination therapy with pembrolizumab and lenvatinib.

The treatment of advanced endometrial cancer is clinically challenging, prompting the exploration of innovative therapeutic strategies such as antibody-drug conjugates (ADC). ADCs, which include mAbs, cytotoxic components, and linkers, demonstrate robust targeting, cytotoxicity, and manageable adverse effects. To provide a thorough understanding of the status of research, this review elucidates promising therapeutic targets in endometrial cancer, such as HER2, folate receptor α, and trophoblast surface antigen-2, and summarizes preclinical and clinical trial data on related ADC drugs in endometrial cancer. We also discuss the toxicity of ADC drugs. Most adverse events arise from cytotoxic components such as microtubule inhibitors and topoisomerase inhibitors. The ocular toxicity may be mainly related to off-target effects of monomethyl auristatin F/DF4 payloads. Interstitial lung disease is a serious adverse event, mainly caused by antibodies, and most of them are of grade 1 to 2 toxicity. Among them, anti-HER2 ADC–induced interstitial pneumonia is commonly dose-dependent. Moreover, we identified potential new targets for endometrial cancer treatment and explored strategies to overcome ADC resistance, such as choosing combination therapy or developing a new generation of ADC drugs. Continuous research and innovation in this field hold promise for improving the survival and overall quality of life of patients with advanced endometrial cancer.

STRO-002 is a novel homogeneous folate receptor alpha (FolRα) targeting antibody–drug conjugate (ADC) currently being investigated in the clinic as a treatment for ovarian and endometrial cancers. Here, we describe the discovery, optimization, and antitumor properties of STRO-002. STRO-002 was generated by conjugation of a novel cleavable 3-aminophenyl hemiasterlin linker-warhead (SC239) to the nonnatural amino acid para-azidomethyl-L-phenylalanine incorporated at specific positions within a high affinity anti-FolRα antibody using Sutro's XpressCF+, which resulted in a homogeneous ADC with a drug–antibody ratio (DAR) of 4. STRO-002 binds to FolRα with high affinity, internalizes rapidly into target positive cells, and releases the tubulin-targeting cytotoxin 3-aminophenyl hemiasterlin (SC209). SC209 has reduced potential for drug efflux via P-glycoprotein 1 drug pump compared with other tubulin-targeting payloads. While STRO-002 lacks nonspecific cytotoxicity toward FolRα-negative cell lines, bystander killing of target negative cells was observed when cocultured with target positive cells. STRO-002 is stable in circulation with no change in DAR for up to 21 days and has a half-life of 6.4 days in mice. A single dose of STRO-002 induced significant tumor growth inhibition in FolRα-expressing xenograft models and patient-derived xenograft models. In addition, combination treatment with carboplatin or Avastin further increased STRO-002 efficacy in xenograft models. The potent and specific preclinical efficacy of STRO-002 supports clinical development of STRO-002 for treating patients with FolRα-expressing cancers, including ovarian, endometrial, and non–small cell lung cancer. Phase I dose escalation for STRO-002 is in progress in ovarian cancer and endometrial cancer patients (NCT03748186 and NCT05200364).